PROJECT SUMMARY Amyloids are fibrous protein assemblies that are thought to play a critical role in the progression of many severe human diseases such as Alzheimer?s, Parkinson?s, and prion diseases. Although amyloids have been predominantly understood in the context of disease as toxic protein deposits, amyloid-like assemblies are beginning to be recognized as having critical physiological functions. In order to facilitate these functions some cells have unknown mechanisms to regulate assembly and clearance of amyloid-like assemblies. My research vision is to discover and understand the pathways and mechanisms by which cells regulate formation, function, and reversibility of amyloids. The basis for these studies is our recent discovery that in order to control translation during meiosis, budding yeast regulates assembly of an RNA-binding protein into structures that have many biochemical properties of amyloid. Knowledge gained from these studies will lead to important advances in our understanding of the causes of neurodegenerative diseases and in time could lead to therapeutic opportunities. A five-year goal of my research is to understand the mechanisms underlying yeast?s remarkable ability to efficiently regulate both formation and clearance of amyloid-like structures. I will also use a combination of in vitro and in vivo approaches to decipher how translation can be regulated by amyloid-like assemblies of RNA- binding proteins. Budding yeast is a powerful experimental system to study these processes. My lab can easily grow populations of cells that rapidly and synchronously produce and clear amyloid-like assemblies. Investigation of functional amyloid-like assemblies provides exciting long-term opportunities in chemical screening and synthetic biology. In collaboration with our core chemical screening facility, my lab will use yeast to screen and identify compounds that prevent and/or disassemble amyloid-like assemblies. I also plan to design synthetic translational repressors based on the hypothesis that specificity and repression are governed by interchangeable protein modules. Furthermore, I will collaborate with other labs in my department to examine mammalian and bacterial proteins that form amyloid-like assemblies. These studies will lay the foundation for understanding the molecular underpinnings of how cells regulate and process amyloid-like assemblies. Despite much research and development, anti-amyloid preventative therapies have been elusive. They are needed for neurodegenerative diseases in which few if any effective preventative therapies are currently available. Therapeutic strategies resulting from this work will rely on my ability to apply the findings we gain from this study to neurodegenerative disease models. Columbia University Medical Center and the Taub Institute for Alzheimer?s and Aging Research provide the supportive framework and collaborative opportunities to make this possible.